ΟρισµόςΚΑ ESC 2008 ΚΑΙ. ΚΑΙ τυπικά. καρδιακής. ανεπάρκειας. 2. Σημεία. 3. Αντικειμενικές αποδείξεις δομικής ή λειτουργικής δυσλειτουργίας της καρδιάς

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Λαμία Αλεξιάδης
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2 Λεωνίδας Ε. Πουλημένος FESC Επιμελητής Β Ε.Σ.Υ. Καρδιολογική Κλινική Γ.Ν. Ασκληπιείο Βούλας ιευθυντής: Καθ. Αθ. Ι. Μανώλης

3 ΟρισµόςΚΑ ESC Τυπικά συμπτώματα καρδιακής ανεπάρκειας (Δύσπνοια στην ηρεμία ή κατά την άσκηση, κόπωση, οιδήματα κάτω άκρων) 2. Σημεία ΚΑΙ τυπικά καρδιακής ανεπάρκειας (Ταχυκαρδία, ταχύπνοια, υγροί ρόγχοι, πλευριτικές συλλογές, αύξηση ΚΦΠ, οιδήματα, ηπατομεγαλία) ΚΑΙ 3. Αντικειμενικές αποδείξεις δομικής ή λειτουργικής δυσλειτουργίας της καρδιάς στην ηρεμία (Μεγαλοκαρδία, S3, φυσήματα, U/S, αύξηση NP)

4 McMurray JJV, et al.

5 ΟρισµόςΚΑ ESC 2012

6 ΣτάδιαΚαρδιακής Ανεπάρκειας

7 Αξιοπιστίαπρογνωστικών προγνωστικών δεικτώνκ.α. Παραδοσιακά αφορούν πληθυσμούς και όχι άτομα Τhe likelihood of survival can be determined reliably only in populations and not in individuals (ACC/AHA Guidelines 2005)

8 Οιδανικόςπρογνωστικός δείκτης Είναι αναπαραγώγιμος Αντανακλά την σοβαρότητα της νόσου Είναι εφαρμόσιμος Σχετίζεται την επιτυχία της θεραπευτικής παρέμβασης

9 Πρόβληµαµε µεµελέτεςµελέτες Το δείγμα είναι περιορισμένο Αφορά ασθενείς με διαφορετική αιτιολογία και σοβαρότητα νόσου Πολλές μεταβλητές δεν είναι ανεξάρτητες μεταξύ τους (π.χ. VO2 CO στην άσκηση) Selection bias (π.χ. Ικανότητα για άσκηση) Διαφορετικοί τρόποι εκτίμησης ίδιας λειτουργίας (π.χ. LVEF) Η εισαγωγή θεραπείας αλλάζει την προγνωστική άξια (π.χ. ΑΜΕΑ, Na) Διάρκεια του Follow Up Εργαστηριακά ή φυσιολογικά (ημερήσια διακύμανση, αλλαγή με την θέση) προβλήματα μέτρησης Στατιστικές ιδιαιτερότητες

χ. LVEF) Η εισαγωγή θεραπείας αλλάζει την προγνωστική άξια (π.χ. ΑΜΕΑ, Na) Διάρκεια του Follow Up Εργαστηριακά ή φυσιολογικά

10 ESC Guidelines Δημογραφικοί και από ιστορικό Κλινικοί Ηλεκτροφυσιολογικοί Λειτουργικοί και Άσκησης Προσδιοριζόμενοι στο αίμα Αιμοδυναμικοί παράγοντες Απεικονιστικοί

11 ΑΙΜΑ ESC 2008 Υψηλές τιµές BNP NTproBNP * Χαµηλό Na + * Αυξηµένη Τροπονίνη* Υψηλοί Βιοδείκτες Νευροχυµική διέγερση Αυξηµένη Cr Αυξηµένη Χολερυθρίνη Αναιµία Αυξηµένο Ουρικό οξύ

12 Biomarker: Definition A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. NIH Biomarkers Definition Working Group. Atkinson, et al. Clin Pharmacol Ther 2001 Discovery Confirmation Validation & Refinement Adoption Identification Established relevance to population Identify clinical utility

NIH Biomarkers Definition Working Group. Atkinson, et al.

13 N Engl J Med 2008;358:

15 Objectives of Biomarker Testing in Heart Failure Diagnosis: 1. To establish or refute a diagnosis 2. To understand the underlying pathophysiologic processes Risk Stratification / Screening: 3. To determine the presence or level of severity of disease 4. To detect adverse consequences Monitoring / Therapeutic Guidance: 5. To guide or monitor responses to treatment. Condition X Outcome A Biomarker Intervention Outcome B

To determine the presence or level of severity of disease 4.

16 Refinement: Criteria for a Clinically Useful Biomarker Can the clinician measure it? Accurate and reproducible methods Rapid turn around Reasonable costs Does it add new information? Strong and consistent association between marker and outcome or disease of interest in multiple studies Decision limits are validated in generalizable populations Will it help with management? Superior performance to existing tests Evidence that it enhances outcomes or process of care Can it be incorporated into workflow? Morrow & Braunwald, Circulation 2007

Strong and consistent association between marker and outcome or disease of interest in multiple studies Decision limits are validated

17 Non-Specific Blood Biomarkers in Heart Failure BUN, creatinine, microalbuminuria Bilirubin, INR, albumin, AST/ALT Fasting cholesterol panel Sodium, potassium Hemoglobin Iron deficiency panel Thyroid panel Uric acid Leukocyte count C-reactive protein Tang W, Biomarkers Med 2009; Braunwald, HF Clin NA 2009

Sodium, potassium Hemoglobin Iron deficiency panel Thyroid panel Uric acid

18 Biomarker Discovery De Couto et al, Nat Rev Cardiol 2010

19 Publications van Kimmenade RRJ, Januzzi JL Jr.. Clin Chem 2012;58(1):

20 οµή ANP BNP CNP ANP aa aa Atria of of heart BNP aa aa Ventricles of of heart C-type NP D-type NP aa aa or or aa aa Vascular endothelium Green mamba snake aa aa venom

C-type NP D-type NP 53 53 aa aa or or 22 22 aa

21 plasma volume (myocardial stretch) ANP / BNP water excretion sodium excretion glomerular filtration rate peripheral vascular resistance plasma osmolality Vasopressin Renin Angiotensin II Aldosterone - - sodium loss - - +

22 Αιµοδυναµικοίκαθοριστές καθοριστές επιπέδων BNP

23 Negative Predictive Value >90% Biosite BNP (pg/ml) Maisel et al N Engl J Med 2002 Roche NT-proBNP Januzzi et al, AJC 2006

24 Increase BNP Increasing age Female gender Renal insufficiency Thyroid disorders Atrial fibrillation Cardiac surgery Anemia Pulmonary hypertension Pulmonary embolism Mitral regurgitation Right ventricular failure Genetic predisposition Beta-blocker therapy (transient) Anti-androgen therapy Decrease BNP Stunning Obesity Diuretics RAAS drugs Troughton et al, J Am Coll Cardiol 2004

25 BASEL IMPROVE-CHF Roche NT-proBNP (pg/ml) Moe et al, Circulation 2007 Biosite BNP (pg/ml) Muller et al, N Engl J Med 2003

26 REDHOT

27 REDHOT 464 ασθενείς με δύσπνοια 90% νοσηλεύτηκαν Κριτήριο εισόδου στη μελέτη η τιμή BNP>100pg/mL Οι κλινικοί ιατροί δε γνώριζαν τα επίπεδα του πεπτιδίου Παρακολούθηση των ασθενών για 90 ημέρες

28 REDHOT Πρόγνωση Maisel A et al. J Am Coll Cardiol 2004;44:

31 BASEL HFSA 2010 Guideline Recommendation IMPROVE-CHF 4.6: It is recommended that BNP or NTproBNP levels be assessed in all patients suspected of having HF, especially when the diagnosis is not certain. Roche NT-proBNP (pg/ml) (Strength of Evidence = A) Moe et al, Circulation 2007 Biosite BNP (pg/ml) Muller et al, N Engl J Med 2003

33 Logeart et al, J Am Coll Cardiol 2004

34 High BNP at Month 4 Low BNP at Month 4 Bayer ADVIA BNP (in pg/ml) Morrow et al, JAMA 2005

35 Risk Stratification: Multimarker Strategy (Serial) Shionogi BNP (pg/ml) Biomarkers in Heart Failure l June 25, 2011 l 35 Miller et al, Circulation 2007

36 New York Heart Association Classification ACC/AHA Staging Olmsted (45+ yrs) IV III II I A B C D Refractory End-Stage HF Marked symptoms at rest despite maximal medical therapy Symptomatic HF Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Asymptomatic HF Previous MI LV systolic dysfunction Asymptomatic valvular disease High Risk for Developing HF Hypertension CAD Diabetes mellitus Family history of cardiomyopathy 0.2 million Established HF Diagnosis 5 million 8-10 million million 0.2% 12% 34% 22% Normals 32% Biomarkers in Heart Failure l June 25, 2011 l 36 Adapted from Jessup et al, Circulation 2009; and Aamer et al, Circulation 2007

37 40 30 Lowest third Middle third Highest third Prevalence (%) EF <50 Valvular disease RWMA Diastolic dysfunction LAE LVH Roche NT-proBNP (pg/ml) McKie et al, Hypertension 2006

38 40 30 HFSA 2010 Guideline Recommendation 4.3: Lowest third Middle third Highest third Routine determination of plasma B-type natriuretic peptide (BNP) or N-terminal pro-bnp (NT-proBNP) concentration as part of a screening evaluation for 10 structural heart disease in asymptomatic patients is not recommended. Prevalence (%) 20 0 EF <50 Valvular disease RWMA Diastolic dysfunction LAE LVH (Strength of Evidence = B) Roche NT-proBNP (pg/ml) McKie et al, Hypertension 2006

40 Current FDA-Cleared Indications for NPs Aid in the diagnosis of individuals suspected of having congestive heart failure (all assays): BNP: 100 pg/ml NT-proBNP: 125 pg/ml Aid in risk stratification: : (Biosite, Siemens, Roche) Acute coronary syndromes: BNP 80 pg/ml; NT-proBNP 240 pg/ml Heart failure: BNP 100 pg/ml; NT-proBNP 1,000 pg/ml Aid in the assessment of increased risk of cardiovascular events and mortality in patients at risk for heart failure who have stable coronary artery disease: : (Roche) NT-proBNP 125 pg/ml

41 Risk-Driven Management: looking back Spot check Identify vulnerability Variety of tools (external / implanted) Event-Directed Management: looking now Interval assessments Alert vulnerability Infrastructure and response solutions needed Goal-Directed Management: looking forward Disease- and therapy-specific Reduce vulnerability Infrastructure and response solutions needed Potential for closed-loop system Samara & Tang, Heart Fail Rev 2011

42 Broadly available Accurate and precise Consist results Responsive to interventions Non-pharmacologic Pharmacologic Reimbursed Whellan et al, Am Heart J Suppl 2007

43 A natriuretic-peptide peptide-guided approach to heart failure therapy Assumption 1: Natriuretic peptides help to identify patients at increased risk of adverse outcomes Assumption 2: A reduction in natriuretic peptide concentration is associated with improved clinical outcomes Assumption 3: Therapies with established benefit in the management of heart failure lower natriuretic peptide concentrations Assumption 4: Elevated natriuretic peptide levels help to identify patients who derive greater benefit from these therapies in the management of heart failure O Donoghue, M. & Braunwald, E. Nat. Rev. Cardiol. 7, (2010)

46 Jourdain P et al. JACC 2007;49:1733 9

47 Natriuretic Peptide-Guided Therapy: BATTLE-SCARRED Richards et al, JACC 2009

48 Natriuretic Peptide-Guided Therapy: PROTECT Patient with Class II-IV IV symptoms, EF 40%, recent HF event Randomization echocardiogram Standard of Care Minnesota Living With HF Questionnaire quarterly Standard of Care + NT-proBNP Minnesota Living With HF Questionnaire quarterly Therapy adjusted to achieve optimal drug targets Visits q3 months Extra visits as needed for treatment goals Therapy adjusted to achieve optimal drug targets PLUS NT-proBNP 1000 pg/ml Visits q3 months Extra visits as needed for treatment goals Close-out out echocardiogram Total cardiovascular events assessed Januzzi et al, AHA Late-Breaking Clinical Trial (2010)

49 Natriuretic Peptide-Guided Therapy: PROTECT 1.0 Log rank P =.03 Number of events Achieved value <1000 pg/ml <2000 pg/ml <3000 pg/ml events Treatment arm SOC NT-proBNP 35.6% 44.3% 57.5% 68.6% 69.9% 80.0% P =.009 SOC Total CV Events 58 events NT-proBNP *Logistic Odds NT-proBNP NT-proBNP probnp= = 0.44 (95% CI= ;.84; P =.019) *Adjusted for age, LVEF, NYHA Class, and egfr Event free survival NT-proBNP (N=75) Standard-of of-care (N=76) Days from enrollment Changes in therapy at follow-up (NT-proBNP vs SOC): Aldo antagonists (63% vs 45%, p=0.001) Loop diuretics (85% vs 96%, p=0.05) Januzzi et al, AHA Late-Breaking Clinical Trial (2010)

Clinicians caring for patients with heart failure are no strangers rs to ambiguity of clinical presentation and imprecision of diagnostic and monitoring tools.

50 Clinicians caring for patients with heart failure are no strangers rs to ambiguity of clinical presentation and imprecision of diagnostic and monitoring tools.. Anyone who demands the ultimate proof or "evidence" for the clinical utility of natriuretic peptide testing should reflect on what evidence should be demanded for a diagnostic test and whether such standards have been imposed on other clinical tests. Tang WH, Circulation Heart Failure 2009

52 European Heart Journal Advance Access published May 7, 2012

56 Maisel A. J Am Coll Cardiol 2011;58(18):

57 Initial Clinical Assessment of Patients Presenting With Heart Failure Measurement of BNP and Noninvasive Imaging I IIa IIb III I IIa IIb III Measurement of natriuretic peptides (B-type natriuretic peptide (BNP) or N-terminal pro-b-type natriuretic peptide (NT-proNBP)) can be useful in the evaluation of patients presenting in the urgent care setting in whom the clinical diagnosis of HF is uncertain. Measurement of natriuretic peptides (BMP and NT-proBNP) can be helpful in risk stratification. Modified Noninvasive imaging may be considered to define the likelihood of coronary artery disease in patients with HF and LV dysfunction. NO CHANGE 57

58 Serial Clinical Assessment of Patients Presenting With Heart Failure Measuring Ejection Fraction and Structural Remodeling I IIa IIb III I IIa IIb III Repeat measurement of EF and the severity of structural remodeling can be useful to provide information in patients with HF who have had a change in clinical status or who have experienced or recovered from a clinical event or received treatment that might have had a significant effect on cardiac function. NO CHANGE The value of serial measurements of BNP to guide therapy for patients with HF is not well established. NO CHANGE 58

59 *In the acute setting, MR-proANP may also be used (cut-off point 120 pmol/l, i.e. <120 pmol/l = heart failure unlikely).

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